In humans the therapeutic use of combinations of the aminoglycoside antibiotic, kanamycin, with either of the diuretics, ethacrynic acid or furosemide, can cause permanent deafness. In order to study this ototoxic drug effect experimentally, we developed an animal model of the interaction between kanamycin and ethacrynic acid. We have used this model to determine the time-dose-effect relationships of the ototoxic action of these drugs. In addition, we have identified the ultrastructural sites within the cochlea at which the earliest damage occurs as a result of this drug interaction. Recently we have found that other aminoglycosides as well as the nonaminoglycosides, viomycin and polymyxin B, produce an ototoxic interaction similar to that of kanamycin when administered in combination with ethacrynic acid. This finding raises the possibility that humans may be at risk of an ototoxic drug interaction from a number of therapeutic agents. Therefore, we propose to screen drugs related to those known to interact in order to establish whether or not they produce a similar effect. We also propose to study the quantitative time-dose-effect relationships of drugs found to interact and to evaluate the morphologic lesion they produce in the cochlea. In addition, we propose to study the mechanism of the kanamycin-ethacrynic acid interaction using histochemical and autoradiographic methods as well as procedures designed to prevent the ototoxic interaction of these drugs.